A crucial component of the US response to the opioid epidemic is expanding the use of medication assisted treatment, most commonly using methadone or buprenorphine, for opioid use disorder. Many persons with opioid use disorder have comorbidities that necessitate treatment with other acutely and chronically used medications, and this proportion is expected to rise with the evolving demographics of the opioid epidemic. Methadone and buprenorphine have pharmaco- kinetic and pharmacodynamic properties that make them highly likely to interact adversely with many other drugs, some of which are very commonly used. Further, past experience demonstrates that existing pharmacologic knowledge is insufficient to predict all clinically important drug-drug interactions. Despite the high potential for and serious consequences of both predicted and unanticipated drug-drug interactions, almost no research has examined the real-world health effects of drugs given concomitantly with methadone or buprenorphine. This presents a striking knowledge gap with large and growing clinical and public health consequences. This project's broad objective is to produce clinically-actionable and biologically-relevant knowledge about which medications interact with methadone and/or buprenorphine. Our work will further elucidate interactions with regard to order of drug initiation, dose-response effects, duration-response effects, and susceptible populations. We will achieve these objectives by: a) performing high-throughput physiologically-based pharmacokinetic screening to predict the degree to which two-drug and three-drug combinations that include methadone or buprenorphine increase biological exposure to those agents; b) performing high-throughput pharmacoepidemiologic screening of two-drug and three-drug combinations that include methadone or buprenorphine with regard to rate of emergency department presentation or hospitalization for opioid overdose and poisoning, opioid adverse effects, and cardiac arrest; c) convening an independent multidisciplinary Expert Panel to review screening results and prioritize potential drug interaction pairs and triads for further investigation; and d) conduct a series of rigorous pharmacoepidemiologic studies to inform causal inferences and thereby generate clinically-actionable evidence on prioritized methadone and buprenorphine drug-drug interactions. This rigorous, innovative study will produce actionable results that will guide the selection of drug therapy in the growing population of persons using methadone or buprenorphine who have comorbidities necessitating treatment.